The Program Project is focused on the bases for individual differences in cognitive decline and brain aging in hippocampal/cortical systems. The primary subjects are pathogen-free male Long-Evans rats, with some additional work using non-human primates to provide a cross-species comparison. The participating investigators will deploy their expertise in anatomical, electrophysiological and molecular biological studies of the hippocampus, a system that also supports cognitive functions in the human brain. An important feature of the research program is the use of brain material from a common source that provides standardized assessments of cognitive function (Animal Resource Core) for the neurobiological studies. A centralized Data Management component of the Core is designed to facilitate within-project and across-project analyses. The five individual projects will focus on four main program objectives. The first objective will compare vulnerability of cortical and subcortical neurons associated with the hippocampal formation, where we have found substantially preserved numbers of neurons, irrespective of age or behavioral status. A third program objective is to examine functional alterations for information encoding, signal transduction, and neural plasticity in the hippocampus and the relation of such changes to hippocampal-dependent cognitive decline. Finally, a fourth program objective is to test specific hypotheses about causes of hippocampal aging. The concept that exposure to oxidative stress is a contributing factor. Our approach has significant potential for increasing our understanding of the aging process and for assessing the therapeutic potential of specific neurobiological interventions.